JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Matching the decay half-life with the biological half-life: ImmunoPET imaging with 44Sc-labeled Cetuximab Fab fragment.
Bioconjug. Chem.
PUBLISHED: 11-13-2014
Show Abstract
Hide Abstract
Scandium-44 (t½ = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report for the first time the room temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR) was generated and conjugated with N-[(R)-2-Amino-3-(p-isothiocyanato-phenyl) propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N?,N?-pentaacetic acid (CHX-A?-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ~12 %ID/g at 4 h post-injection) of 44Sc-CHX-A?-DTPA-Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. This successful strategy for immunoPET imaging of EGFR expression using 44Sc-CHX-A?-DTPA-Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also monitor the therapeutic efficacy of anti-EGFR treatments.
Related JoVE Video
VEGF121-Conjugated Mesoporous Silica Nanoparticle: A Tumor Targeted Drug Delivery System.
ACS Appl Mater Interfaces
PUBLISHED: 10-30-2014
Show Abstract
Hide Abstract
The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling cascade plays a critical role in tumor angiogenesis and metastasis and has been correlated with several poorly prognostic cancers such as malignant gliomas. Although a number of anti-VEGFR therapies have been conceived, inefficient drug administration still limits their therapeutic efficacy and raises concerns of potential side effects. In the present work, we propose the use of uniform mesoporous silica nanoparticles (MSNs) for VEGFR targeted positron emission tomography imaging and delivery of the anti-VEGFR drug (i.e., sunitinib) in human glioblastoma (U87MG) bearing murine models. MSNs were synthesized, characterized and modified with polyethylene glycol, anti-VEGFR ligand VEGF121 and radioisotope (64)Cu, followed by extensive in vitro, in vivo and ex vivo studies. Our results demonstrated that a significantly higher amount of sunitinib could be delivered to the U87MG tumor by targeting VEGFR when compared with the non-targeted counterparts. The as-developed VEGF121-conjugated MSN could become another attractive nanoplatform for the design of future theranostic nanomedicine.
Related JoVE Video
Targeting JAK1/STAT3 signaling suppresses tumor progression and metastasis in a peritoneal model of human ovarian cancer.
Mol. Cancer Ther.
PUBLISHED: 10-15-2014
Show Abstract
Hide Abstract
JAK/STAT3 is one of the major signaling pathways that is aberrantly activated in ovarian cancer and associated with tumor progression and poor prognosis in ovarian cancer patients. In this study, we evaluated the therapeutic potential of targeting JAK/STAT3 signaling in ovarian cancer using a peritoneal dissemination mouse model. We developed this mouse model by injecting a metastatic human ovarian cancer cell line, SKOV3-M-Luc, into the peritoneal cavity of immunodeficient mice. This model displayed a phenotype similar to late stage ovarian cancer, including extensive peritoneal metastasis and ascites production. The constitutive activation of STAT3 in human ovarian cancer cells appeared to be mediated by an autocrine-cytokine loop involving the IL-6 family of cytokines and JAK1 kinase. shRNA-mediated knockdown of JAK1 or STAT3 in ovarian cancer cells led to reduced tumor growth, decreased peritoneal dissemination and diminished ascites production, suggesting a critical role of STAT3 in ovarian cancer progression. Similar results were obtained when a small-molecule inhibitor (JAKi) of the JAK1 kinase was used to treat ovarian cancer in this model. In addition, we found that the expression level of IL-6 was correlated with activation of STAT3 in ovarian cancer cells both in vitro and in vivo, suggesting a potential application of IL-6 as a biomarker. Altogether, our results demonstrate that targeting JAK1/STAT3, using shRNA knockdown or a small molecule inhibitor, effectively suppressed ovarian tumor progression and, therefore, could be a potential novel therapeutic approach for treating advanced ovarian cancer.
Related JoVE Video
[Phenolic constituents from Oplopanax horridus].
Zhongguo Zhong Yao Za Zhi
PUBLISHED: 10-07-2014
Show Abstract
Hide Abstract
The chemical constituents were isolated and purified by various chromatographic techniques indluding silica gel, reverse phase silica gel, sephadex LH-20 and pre-HPLC and identified by their physicochemical properties and spectral data. Sixteen phenolic compounds had been isolated and n-butanol extracts which were fractionated from the ethanol extract of Oplopanax horridus roots bark. Their structures were identified as below, including 7 phenylpropanoid compounds, ferulic acid (1), 3-acetylcaffeic acid (2), caffeic acid (3), homovanillyl alcohol 4-O-beta-D-glucopyranoside (4), 3-hydroxyphenethyl alcohol 4-O-beta-D-glucopyranoside (5), 3, 5-dimethoxycinnamyl alcohol 4-O-beta-D-glucopyranoside (6), and 3-dimethoxycinnamyl alcohol 4-O-beta-D-glucopyranoside (7). Three coumarins, scopoletin (8), esculetin (9) and 3'-angeloyl-4'-acetyl-cis-knellactone (10). And 6 lignan compounds, (+)-isolaricires-inol-9'-O-beta-D-glucopyranoside (11), 3, 3'-dimethoxy-4, 9, 9'-trihydroxy-4', 7-epoxy-5', 8-lignan-4, 9-bis-O-beta-D-glucopyranoside (12), (+)-5, 5'-dimethoxylariciresinol 4'-O-beta-D-glucopyranoside (13), (-)-5,5'-dimethoxylariciresinol 4'-O-beta-D-glucopyranoside (14), (-)-pinoresinol 4'-O-beta-D-glucopyranoside (15), and (+)-5, 5'-dimethoxylariciresinol 9'-O-beta-D-glucopyranoside (16). All compounds were isolated and identified for the first time from this plant All the constituents except compounds 4, 6, 12 and 13 were obtained for the first time from the genus Oplopanax.
Related JoVE Video
Effect of CYP2C9-VKORC1 interaction on warfarin stable dosage and its predictive algorithm.
J Clin Pharmacol
PUBLISHED: 09-04-2014
Show Abstract
Hide Abstract
This study aimed to identify the effect of CYP2C9-VKORC1 interaction on warfarin dosage requirement and its predictive algorithm by investigating four populations. Generalized linear model was used to evaluate the relationship between the interaction and warfarin stable dosage (WSD), whereas multiple linear regression analysis was applied to construct the WSD predictive algorithm. To evaluate the effect of CYP2C9-VKORC1 interaction on the predictive algorithms, we compared the algorithms with and without the interaction. The interaction was significantly associated with WSD in the Chinese and White cohorts (P values?
Related JoVE Video
Generation and Screening of Monoclonal Antibodies for ImmunoPET Imaging of IGF1R in Prostate Cancer.
Mol. Pharm.
PUBLISHED: 09-04-2014
Show Abstract
Hide Abstract
Insulin-like growth factor 1 receptor (IGF1R) plays an important role in proliferation, apoptosis, angiogenesis, and tumor invasion. The expression level of IGF1R is related to resistance to several targeted therapies. The goal of this study was to develop an immunoPET tracer for imaging of IGF1R in prostate cancer. Murine antibodies against human IGF1R were generated in BALB/c mice, which were screened in IGF1R-positive MCF-7 cells using flow cytometry as well as biodistribution studies with multiple (64)Cu-labeled antibody clones. The antibody production method we adopted could readily produce milligram quantities of anti-IGF1R antibodies for in vivo studies. One antibody clone (1A2G11) with the highest affinity for IGF1R was selected and conjugated to NOTA for (64)Cu-labeling. NOTA-1A2G11 maintained IGF1R specificity/avidity based on flow cytometry. (64)Cu-labeling was achieved with good yield (>50%) and high specific activity (>1 Ci/?mol). Serial PET imaging revealed that uptake of (64)Cu-NOTA-1A2G11 was 2.8 ± 0.7, 10.2 ± 2.6, and 9.6 ± 1.7 %ID/g in IGF1R-positive DU-145 tumors at 4, 24, and 48 h postinjection, respectively (n = 3), significantly higher than that in IGF1R-negative LNCaP tumors (<3 %ID/g at each time point) except at 4 h postinjection. Histology studies showed strong correlations between IGF1R expression level in the prostate cancer tumor tissues and tumor uptake of (64)Cu-NOTA-1A2G11. Prominent, persistent, and IGF1R-specific uptake of (64)Cu-NOTA-1A2G11 in IGF1R-positive prostate tumors holds strong potential for future cancer diagnosis, prognosis, and therapy using this antibody.
Related JoVE Video
Image-Guided Drug Delivery with Single-Photon Emission Computed Tomography: A Review of Literature.
Curr Drug Targets
PUBLISHED: 09-02-2014
Show Abstract
Hide Abstract
Tremendous resources are being invested all over the world for prevention, diagnosis, and treatment of various types of cancer. Successful cancer management depends on accurate diagnosis of the disease along with precise therapeutic protocol. The conventional systemic drug delivery approaches generally cannot completely remove the competent cancer cells without surpassing the toxicity limits to normal tissues. Therefore, development of efficient drug delivery systems holds prime importance in medicine and healthcare. Also, molecular imaging can play an increasingly important and revolutionizing role in disease management. Synergistic use of molecular imaging and targeted drug delivery approaches provides unique opportunities in a relatively new area called 'image-guided drug delivery' (IGDD). Single-photon emission computed tomography (SPECT) is the most widely used nuclear imaging modality in clinical context and is increasingly being used to guide targeted therapeutics. The innovations in material science have fueled the development of efficient drug carriers based on, polymers, liposomes, micelles, dendrimers, microparticles, nanoparticles, etc. Efficient utilization of these drug carriers along with SPECT imaging technology have the potential to transform patient care by personalizing therapy to the individual patient, lessening the invasiveness of conventional treatment procedures and rapidly monitoring the therapeutic efficacy. SPECT-IGDD is not only effective for treatment of cancer but might also find utility in management of several other diseases. Herein, we provide a concise overview of the latest advances in SPECT-IGDD procedures and discuss the challenges and opportunities for advancement of the field.
Related JoVE Video
Luteolin potentiates the sensitivity of colorectal cancer cell lines to oxaliplatin through the PPAR?/OCTN2 pathway.
Anticancer Drugs
PUBLISHED: 07-31-2014
Show Abstract
Hide Abstract
Oxaliplatin is a chemotherapeutic agent used in the treatment of colorectal cancers. However, the mechanism controlling the cellular uptake and efflux of oxaliplatin is not completely understood. Organic cation/carnitine transporter 2 (OCTN2) is a member of the solute carrier superfamily and is a determinant of oxaliplatin uptake. OCTN2 is regulated by peroxisome proliferator-activated receptor ? (PPAR?) binding to the PPAR-response element within the first intron. Luteolin is a naturally occurring flavonoid and an agonist of PPAR?. Thus, we hypothesize that luteolin-mediated OCTN2 expression and activity potentiate the sensitivity of cancer cells to oxaliplatin. In this study, luteolin increased mRNA and protein expression of OCTN2 in a time-dependent and dose-dependent manner in colorectal cancer SW480 cells. This induction was attenuated by PPAR? antagonist GW9662 as well as by PPAR? knockdown, suggesting that the induction by luteolin is dependent on PPAR?. In uptake studies, luteolin increased the binding affinity of OCTN2 toward oxaliplatin and enhanced intracellular concentration of oxaliplatin. This finding is likely because of the increase of PDZ domain containing 1 (PDZK1) and PDZ domain containing 3 (PDZK2), which are known to facilitate the expression of OCTN2 on the cell surface and/or enhance transporter activity. Moreover, cell viability and cell apoptosis assays showed that luteolin increased oxaliplatin uptake and intracellular accumulation through OCTN2. Thus, our study showed that luteolin increased the sensitivity of colorectal cancer SW480 cells to oxaliplatin, likely through the PPAR?/OCTN2 pathway.
Related JoVE Video
Induction of human CYP3A4 by huperzine A, ligustrazine and oridonin through pregnane X receptor-mediated pathways.
Pharmazie
PUBLISHED: 07-31-2014
Show Abstract
Hide Abstract
The pregnane X receptor (PXR) is a key regulator of CYP3A4, which is involved in catalyzing the metabolic conversion of a number of endogenous substrates. In this study, we screened 22 compounds isolated from traditional Chinese herbal medicines using luciferase reporter gene assays for inspecting their capabilities in inducing PXR-mediated transactivation of CYP3A4 expression. In addition, the mRNA and protein expressions of CYP3A4 and PXR as well as the enzymatic activites of CYP3A4 were analyzed by real-time PCR, Western blot analysis and UPLC-MS/MS-based metabolite assay in LS174T cells. Huperzine A, ligustrazine and oridonin were identified to be the inducers of CYP3A4. These compounds induced the CYP3A4 reporter luciferase activity, and up-regulated CYP3A4 mRNA and protein levels significantly. Besides, huperzine A, ligustrazine and oridonin significantly up-regulated enzymatic activities of CYP3A4. However, the three compounds showed no effects on PXR mRNA and protein expression. To our knowledge, it is the first identification of these three compounds as PXR activators to induce CYP3A4. These results indicate that huperzine A, ligustrazine and oridonin induced CYP3A4 expression and activation via PXR dependent pathways, and might contribute to drug-drug interactions.
Related JoVE Video
(44)Sc: an attractive isotope for peptide-based PET imaging.
Mol. Pharm.
PUBLISHED: 07-23-2014
Show Abstract
Hide Abstract
The overexpression of integrin ?v?3 has been linked to tumor aggressiveness and metastasis in several cancer types. Because of its high affinity, peptides containing the arginine-glycine-aspartic acid (RGD) motif have been proven valuable vectors for noninvasive imaging of integrin ?v?3 expression and for targeted radionuclide therapy. In this study, we aim to develop a (44)Sc-labeled RGD-based peptide for in vivo positron emission tomography (PET) imaging of integrin ?v?3 expression in a preclinical cancer model. High quality (44)Sc (t1/2, 3.97 h; ?(+) branching ratio, 94.3%) was produced inexpensively in a cyclotron, via proton irradiation of natural Ca metal targets, and separated by extraction chromatography. A dimeric cyclic-RGD peptide, (cRGD)2, was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and radiolabeled with (44)Sc in high yield (>90%) and specific activity (7.4 MBq/nmol). Serial PET imaging of mice bearing U87MG tumor xenografts showed elevated (44)Sc-DOTA-(cRGD)2 uptake in the tumor tissue of 3.93 ± 1.19, 3.07 ± 1.17, and 3.00 ± 1.25 %ID/g at 0.5, 2, and 4 h postinjection, respectively (n = 3), which were validated by ex vivo biodistribution experiments. The integrin ?v?3 specificity of the tracer was corroborated, both in vitro and in vivo, by competitive cell binding and receptor blocking assays. These results parallel previously reported studies showing similar tumor targeting and pharmacokinetic profiles for dimeric cRGD peptides labeled with (64)Cu or (68)Ga. Our findings, together with the advantageous radionuclidic properties of (44)Sc, capitalize on the relevance of this isotope as an attractive alternative isotope to more established radiometals for small molecule-based PET imaging, and as imaging surrogate of (47)Sc in theranostic applications.
Related JoVE Video
In Vivo Tumor Vasculature Targeted PET/NIRF Imaging with TRC105(Fab)-Conjugated, Dual-Labeled Mesoporous Silica Nanoparticles.
Mol. Pharm.
PUBLISHED: 06-25-2014
Show Abstract
Hide Abstract
Multifunctional mesoporous silica nanoparticles (MSN) with well-integrated multimodality imaging properties have generated increasing research interest in the past decade. However, limited progress has been made in developing MSN-based multimodality imaging agents to image tumors. We describe the successful conjugation of, copper-64 ((64)Cu, t1/2 = 12.7 h), 800CW (a near-infrared fluorescence [NIRF] dye), and TRC105 (a human/murine chimeric IgG1 monoclonal antibody) to the surface of MSN via well-developed surface engineering procedures, resulting in a dual-labeled MSN for in vivo targeted positron emission tomography (PET) imaging/NIRF imaging of the tumor vasculature. Pharmacokinetics and tumor targeting efficacy/specificity in 4T1 murine breast tumor-bearing mice were thoroughly investigated through various in vitro, in vivo, and ex vivo experiments. Dual-labeled MSN is an attractive candidate for future cancer theranostics.
Related JoVE Video
Cloning and characterisation of JAZ gene family in Hevea brasiliensis.
Plant Biol (Stuttg)
PUBLISHED: 06-08-2014
Show Abstract
Hide Abstract
Mechanical wounding or treatment with exogenous jasmonates (JA) induces differentiation of the laticifer in Hevea brasiliensis. JA is a key signal for latex biosynthesis and wounding response in the rubber tree. Identification of JAZ (jasmonate ZIM-domain) family of proteins that repress JA responses has facilitated rapid progress in understanding how this lipid-derived hormone controls gene expression and related physiological processes in plants. In this work, the full-length cDNAs of six JAZ genes were cloned from H. brasiliensis (termed HbJAZ). These HbJAZ have different lengths and sequence diversity, but all of them contain Jas and ZIM domains, and two of them contain an ERF-associated amphiphilic repression (EAR) motif in the N-terminal. Real-time RT-PCR analyses revealed that HbJAZ have different expression patterns and tissue specificity. Four HbJAZ were up-regulated, one was down-regulated, while two were less effected by rubber tapping treatment, suggesting that they might play distinct roles in the wounding response. A yeast two-hybrid assay revealed that HbJAZ proteins interact with each other to form homologous or heterogeneous dimer complexes, indicating that the HbJAZ proteins may expand their function through diverse JAZ-JAZ interactions. This work lays a foundation for identification of the JA signalling pathway and molecular mechanisms of latex biosynthesis in rubber trees. This article is protected by copyright. All rights reserved.
Related JoVE Video
Positron emission tomography image-guided drug delivery: current status and future perspectives.
Mol. Pharm.
PUBLISHED: 06-04-2014
Show Abstract
Hide Abstract
Positron emission tomography (PET) is an important modality in the field of molecular imaging, which is gradually impacting patient care by providing safe, fast, and reliable techniques that help to alter the course of patient care by revealing invasive, de facto procedures to be unnecessary or rendering them obsolete. Also, PET provides a key connection between the molecular mechanisms involved in the pathophysiology of disease and the according targeted therapies. Recently, PET imaging is also gaining ground in the field of drug delivery. Current drug delivery research is focused on developing novel drug delivery systems with emphasis on precise targeting, accurate dose delivery, and minimal toxicity in order to achieve maximum therapeutic efficacy. At the intersection between PET imaging and controlled drug delivery, interest has grown in combining both these paradigms into clinically effective formulations. PET image-guided drug delivery has great potential to revolutionize patient care by in vivo assessment of drug biodistribution and accumulation at the target site and real-time monitoring of the therapeutic outcome. The expected end point of this approach is to provide fundamental support for the optimization of innovative diagnostic and therapeutic strategies that could contribute to emerging concepts in the field of "personalized medicine". This review focuses on the recent developments in PET image-guided drug delivery and discusses intriguing opportunities for future development. The preclinical data reported to date are quite promising, and it is evident that such strategies in cancer management hold promise for clinically translatable advances that can positively impact the overall diagnostic and therapeutic processes and result in enhanced quality of life for cancer patients.
Related JoVE Video
Non-invasive multimodal functional imaging of the intestine with frozen micellar naphthalocyanines.
Nat Nanotechnol
PUBLISHED: 06-02-2014
Show Abstract
Hide Abstract
There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and provide good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ? 20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1,000). Unlike conventional chromophores, nanonaps exhibit non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole-body imaging.
Related JoVE Video
Epigenetic perspectives on cancer chemotherapy response.
Pharmacogenomics
PUBLISHED: 05-07-2014
Show Abstract
Hide Abstract
Epigenetic programs are now widely recognized as being critical to the biological processes of cancer genesis. However, it has not been comprehensively understood how and to what degree they can influence anticancer drugs responses. The development of drugs targeting epigenetic regulation has generated great enthusiasm, with a growing number in clinical development. We highlight here that epigenetic modifications can be involved in the regulation of genes responsible for the absorption, distribution, metabolism and excretion of drugs and for the pathological progression of cancer, thereby affecting anticancer drug responses. The major epigenetic regulatory mechanisms are reviewed, including DNA methylation, miRNA regulation and histone modification, with the aim of promoting rational use of anticancer drugs in the clinic and epigenetic drug development.
Related JoVE Video
Inhibitory effects of phytochemicals on metabolic capabilities of CYP2D6(*)1 and CYP2D6(*)10 using cell-based models in vitro.
Acta Pharmacol. Sin.
PUBLISHED: 05-03-2014
Show Abstract
Hide Abstract
Herbal products have been widely used, and the safety of herb-drug interactions has aroused intensive concerns. This study aimed to investigate the effects of phytochemicals on the catalytic activities of human CYP2D6(*)1 and CYP2D6(*)10 in vitro.
Related JoVE Video
Montelukast rescues primary neurons against A?1-42-induced toxicity through inhibiting CysLT1R-mediated NF-?B signaling.
Neurochem. Int.
PUBLISHED: 04-30-2014
Show Abstract
Hide Abstract
Amyloid-? peptide (A?), which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimer's disease (AD). Montelukast, known as a cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is currently used for treatment of inflammatory diseases such as asthma. We have previously reported that CysLT1R activation is involved in A? generation. In this study, we investigated rescuing effect of CysLT1R antagonist montelukast on A?1-42-induced neurotoxicity in primary neurons. Our data showed that A?1-42 elicited a marked increase of CysLT1R expression in primary mouse neurons. This increment of CysLT1R expression was accompanied by increases of inflammatory factors such as NF-?B p65, tumor necrosis factor-? (TNF?) and interleukin-1? (IL-1?) as well as pro-apoptotic protein Caspase-3 activation and anti-apoptosis protein Bcl-2 reduction. A?1-42-mediated increase of CysLT1R expression was associated with A?1-42-induced cytotoxicity as measured by MTT reduction assay and lactate dehydrogenase (LDH) release assay. This observation was confirmed with treatment of montelukast, a selective CysLT1R antagonist, which had significant effect on A?1-42-induced cytotoxicity. Moreover, blockade of CysLT1R with montelukast reversed A?1-42-mediated increase of CysLT1R expression, and concomitant changes of the pro-inflammatory factors and the apoptosis-related proteins. The results demonstrate that montelukast rescued neurons against A?1-42-induced neurotoxicity, neuroinflammation and apoptosis by down-regulating CysLT1R-mediated NF-?B signaling, suggesting that CysLT1R may be a potential target for AD, and its antagonist may have beneficial effects for treatment of AD.
Related JoVE Video
Design and applications of bispecific heterodimers: molecular imaging and beyond.
Mol. Pharm.
PUBLISHED: 04-28-2014
Show Abstract
Hide Abstract
Ligand-based molecular imaging probes have been designed with high affinity and specificity for monitoring biological process and responses. Single-target recognition by traditional probes can limit their applicability for disease detection and therapy because synergistic action between disease mediators and different receptors is often involved in disease progression. Consequently, probes that can recognize multiple targets should demonstrate higher targeting efficacy and specificity than their monospecific peers. This concept has been validated by multiple bispecific heterodimer-based imaging probes that have demonstrated promising results in several animal models. This review summarizes the design strategies for bispecific peptide- and antibody-based heterodimers and their applications in molecular targeting and imaging. The design and application of bispecific heterodimer-conjugated nanomaterials are also discussed.
Related JoVE Video
JAZF1 regulates visfatin expression in adipocytes via PPAR? and PPAR?/? signaling.
Metab. Clin. Exp.
PUBLISHED: 04-20-2014
Show Abstract
Hide Abstract
Current whole genome-wide association study has identified the association of JAZF1 with type 2 diabetes; its close relation with glucose and lipid metabolism has also been revealed. However, to date, JAZF1 remains a relatively new gene with unknown function.
Related JoVE Video
Rs495828 polymorphism of the ABO gene is a predictor of enalapril-induced cough in Chinese patients with essential hypertension.
Pharmacogenet. Genomics
PUBLISHED: 04-19-2014
Show Abstract
Hide Abstract
ABO genetic polymorphisms have recently been associated with angiotensin-converting enzyme (ACE) activity and inflammation, which play a critical role in the pathogenic mechanism of ACE inhibitor-induced cough. Therefore, the current study determined the association of ABO genetic polymorphisms with enalapril-induced cough in Chinese patients with essential hypertension.
Related JoVE Video
Effects of eNOS rs1799983 and ACE rs4646994 polymorphisms on the therapeutic efficacy of salvianolate injection in Chinese patients with coronary heart disease.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 04-18-2014
Show Abstract
Hide Abstract
The purpose of the present study was to clarify the association of eNOS 894G/T and ACE I/D genetic polymorphisms with the risk of coronary heart disease (CHD) and to explore the effects of these polymorphisms on the therapeutic efficacy of salvianolate injection in Chinese CHD patients. In all, 153 CHD patients and 198 healthy controls were enrolled in the study. We collected 5 mL peripheral blood for DNA extraction. Genetic diagnosis of eNOS 894G/T was determined by direct sequencing. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to detect ACE I/D genotypes. We observed significant differences in the frequency distribution of eNOS and ACE polymorphisms between CHD patients and healthy controls (P < 0.05). Binary logistic regression stepwise analysis revealed that the genotypes had an additive and dominant effect on patients' therapeutic responses (P < 0.05). These data suggest that the genetic polymorphisms of ACE I/D and eNOS 894G/T probably play a role in the development of CHD and these genetic polymorphisms may affect the response to salvianolate injection in Chinese CHD patients.
Related JoVE Video
New radiotracers for imaging of vascular targets in angiogenesis-related diseases.
Adv. Drug Deliv. Rev.
PUBLISHED: 04-12-2014
Show Abstract
Hide Abstract
Tremendous advances over the last several decades in positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for targeted imaging of molecular and cellular events in the living systems. Angiogenesis, a multistep process regulated by the network of different angiogenic factors, has attracted world-wide interests, due to its pivotal role in the formation and progression of different diseases including cancer, cardiovascular diseases (CVD), and inflammation. In this review article, we will summarize the recent progress in PET or SPECT imaging of a wide variety of vascular targets in three major angiogenesis-related diseases: cancer, cardiovascular diseases, and inflammation. Faster drug development and patient stratification for a specific therapy will become possible with the facilitation of PET or SPECT imaging and it will be critical for the maximum benefit of patients.
Related JoVE Video
Anticancer activities of polyynes from the root bark of Oplopanax horridus and their acetylated derivatives.
Molecules
PUBLISHED: 04-12-2014
Show Abstract
Hide Abstract
Six polyynes OH-1~6, some of which are occur naturally in acetylated form, had been isolated and identified from the root bark of Oplopanax horridus (Devil's Club), a natural dietary supplement and medicinal plant in North America. During the evaluation of the polyynes' potential anticancer activities, sixteen more acetylated derivatives OHR-1~16 have synthesized and their anti-proliferation activity on MCF-7, MDA-MB-231, A549, HepG2 and LO2 cells assayed to elucidate their structure-activity relationships. The results showed that OH-1 ((3S, 8S)-falcarindiol) had the most potent anticancer activity, with IC50 values of 15.3, 23.5, 7.7 and 4.7 ?M on MCF-7, A549, HepG2 and MDA-MB-231 cells, respectively. For the primary structure-activity relationship, the anticancer activities of polyynes become weaker if their hydroxyl groups are acetylated, the terminal double bonds transformed into single bonds or they contain one more methylene group in the main skeleton chain.
Related JoVE Video
Engineering of hollow mesoporous silica nanoparticles for remarkably enhanced tumor active targeting efficacy.
Sci Rep
PUBLISHED: 04-01-2014
Show Abstract
Hide Abstract
Hollow mesoporous silica nanoparticle (HMSN) has recently gained increasing interests due to their tremendous potential as an attractive nano-platform for cancer imaging and therapy. However, possibly due to the lack of efficient in vivo targeting strategy and well-developed surface engineering techniques, engineering of HMSN for in vivo active tumor targeting, quantitative tumor uptake assessment, multimodality imaging, biodistribution and enhanced drug delivery have not been achieved to date. Here, we report the in vivo tumor targeted positron emission tomography (PET)/near-infrared fluorescence (NIRF) dual-modality imaging and enhanced drug delivery of HMSN using a generally applicable surface engineering technique. Systematic in vitro and in vivo studies have been performed to investigate the stability, tumor targeting efficacy and specificity, biodistribution and drug delivery capability of well-functionalized HMSN nano-conjugates. The highest uptake of TRC105 (which binds to CD105 on tumor neovasculature) conjugated HMSN in the 4T1 murine breast cancer model was ~10%ID/g, 3 times higher than that of the non-targeted group, making surface engineered HMSN a highly attractive drug delivery nano-platform for future cancer theranostics.
Related JoVE Video
The Effects of Lycopene on the Methylation of the GSTP1 Promoter and Global Methylation in Prostatic Cancer Cell Lines PC3 and LNCaP.
Int J Endocrinol
PUBLISHED: 03-28-2014
Show Abstract
Hide Abstract
DNA (cytosine-5-) methylation silencing of GSTP1 function occurs in prostate adenocarcinoma (PCa). Previous studies have shown that there is an inverse relationship between dietary lycopene intake and the risk of PCa. However, it is unknown whether lycopene reactivates the tumor suppressor gene glutathioneS-transferase-? (GSTP1) by demethylation of the hypermethylated CpGs that act to silence the GSTP1 promoter. Here, we demonstrated that lycopene treatment significantly decreased the methylation levels of the GSTP1 promoter and increased the mRNA and protein levels of GSTP1 in an androgen-independent PC-3 cell line. In contrast, lycopene treatment did not demethylate the GSTP1 promoter or increase GSTP1 expression in the androgen-dependent LNCaP cell line. DNA methyltransferase (DNMT) 3A protein levels were downregulated in PC-3 cells following lycopene treatment; however, DNMT1 and DNMT3B levels were unchanged. Furthermore, the long interspersed element (LINE-1) and short interspersed element ALU were not demethylated when treated by lycopene. In LNCaP cells, lycopene treatment did not affect any detected DNMT protein expression, and the methylation levels of LINE-1 and ALU were decreased. These results indicated that the protective effect of lycopene on the prostate is different between androgen-dependent and androgen-independent derived PCa cells. Further, in vivo studies should be conducted to confirm these promising results and to evaluate the potential role of lycopene in the protection of the prostate.
Related JoVE Video
Telmisartan treatment ameliorates memory deficits in streptozotocin-induced diabetic mice via attenuating cerebral amyloidosis.
J. Pharmacol. Sci.
PUBLISHED: 03-27-2014
Show Abstract
Hide Abstract
Telmisartan, an angiotensin II type 1-receptor blocker (ARBs), has been reported to exert beneficial effects on the central nervous system (CNS). However, the effect of telmisartan on cognitive impairment associated with type 1 diabetes is not well known. Here, we examined the possibility that telmisartan could improve memory function in a type 1 diabetic mouse model, streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice subjected to the Morris Water Maze (MWM) task exhibited a significant decline of spatial learning and memory. Oral administration of telmisartan at two nonhypotensive doses (0.7 or 0.35 mg/kg) significantly improved memory deficits in STZ-induced diabetic mice. Telmisartan treatment markedly reduced A???, APP, BACE1, RAGE, and NF-?B p65 of the hippocampus and cortex, but did not beneficially affect hyperglycemia and hypoinsulinemia in the STZ-induced diabetic mice compared with untreated diabetic mice. Taken together, our findings suggest that telmisartan ameliorates memory deficits in type 1 diabetic mice, at least partly because of attenuation of amyloidosis in the brain.
Related JoVE Video
Theranostic Unimolecular Micelles Based on Brush-Shaped Amphiphilic Block Copolymers for Tumor-Targeted Drug Delivery and Positron Emission Tomography Imaging.
ACS Appl Mater Interfaces
PUBLISHED: 03-18-2014
Show Abstract
Hide Abstract
Brush-shaped amphiphilic block copolymers were conjugated with a monoclonal antibody against CD105 (i.e., TRC105) and a macrocyclic chelator for (64)Cu-labeling to generate multifunctional theranostic unimolecular micelles. The backbone of the brush-shaped amphiphilic block copolymer was poly(2-hydroxyethyl methacrylate) (PHEMA) and the side chains were poly(l-lactide)-poly(ethylene glycol) (PLLA-PEG). The doxorubicin (DOX)-loaded unimolecular micelles showed a pH-dependent drug release profile and a uniform size distribution. A significantly higher cellular uptake of TRC105-conjugated micelles was observed in CD105-positive human umbilical vein endothelial cells (HUVEC) than nontargeted micelles due to CD105-mediated endocytosis. In contrast, similar and extremely low cellular uptake of both targeted and nontargeted micelles was observed in MCF-7 human breast cancer cells (CD105-negative). The difference between the in vivo tumor accumulation of (64)Cu-labeled TRC105-conjugated micelles and that of nontargeted micelles was studied in 4T1 murine breast tumor-bearing mice, by serial positron emission tomography (PET) imaging and validated by biodistribution studies. These multifunctional unimolecular micelles offer pH-responsive drug release, noninvasive PET imaging capability, together with both passive and active tumor-targeting abilities, thus making them a desirable nanoplatform for cancer theranostics.
Related JoVE Video
Association of HMGB1 and HMGB2 genetic polymorphisms with lung cancer chemotherapy response.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 03-17-2014
Show Abstract
Hide Abstract
The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum-based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non-responders) were recruited to the study. All patients received at least two cycles of first-line platinum-based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum-based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum-based chemotherapy response for the subgroup of patients aged >55 years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum-based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum-based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum-based chemotherapy.
Related JoVE Video
Association of nitric oxide synthase 3 (NOS3) 894 G>T polymorphism with prognostic outcomes of anthracycline in Chinese patients with acute myeloid leukaemia.
Clin. Exp. Pharmacol. Physiol.
PUBLISHED: 03-13-2014
Show Abstract
Hide Abstract
The aim of the present study was to investigate the influence of the nitric oxide synthase 3 (NOS3) 894 G>T polymorphism on prognostic outcomes of anthracycline in Chinese patients with de novo intermediate-risk acute myeloid leukaemia (AML) and to examine the gene expression level in relation to genetic variation. In all, 225 Chinese patients with intermediate-risk AML (at the complete remission stage) treated with anthracycline were enrolled in the study. The 894 G>T polymorphism of the NOS3 gene was analysed by allele-specific matrix-assisted laser desorption ionization time-of-flight. Expression of NOS3 mRNA was tested in 72 patients of known genotype for NOS3 894 G>T. The clinical characteristics of these patients were obtained from medical records. Survival analysis showed that patients with AML (GG genotype) had a longer overall survival (OS; P = 0.006). After adjusting for age, gender, leucocyte count, haemoglobin level, platelet level, French, American and Britain (FAB) classification, lactate dehydrogenase levels, Eastern Cooperative Oncology Group Performance Status, nucleophosmin gene and fms-related tyrosine kinase 3 gene, multivariate survival analysis showed that the NOS3 894 G>T polymorphism appeared to be a predicting factor for OS (P = 0.014; hazard ratio = 1.856). However, no significant associations between the NOS3 894 G>T polymorphism and relapse-free survival and relapse in patients with AML were observed. Gene expression levels were significantly higher in patients with the GG genotype than in patients with the GT and TT genotypes (P = 0.033). The findings suggest that the NOS3 894 G>T variant may be a biomarker for the prediction of OS in Chinese patients with AML.
Related JoVE Video
Dose-response of oridonin on hepatic cytochromes P450 mRNA expression and activities in mice.
J Ethnopharmacol
PUBLISHED: 03-08-2014
Show Abstract
Hide Abstract
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. The effects of oridonin on drug processing genes, such as cytochrome P450 and nuclear receptors, were still unclear. Therefore, the present study investigated the influence of oridonin on the hepatic drug metabolizing system to evaluate the safety through its drug interaction potential.
Related JoVE Video
Association of ABCB1 polymorphisms with the efficacy of ondansetron in chemotherapy-induced nausea and vomiting.
Clin Ther
PUBLISHED: 02-25-2014
Show Abstract
Hide Abstract
Resistance to the antiemetic ondansetron is still a major problem resulting in discomfort and poor compliance with chemotherapy in acute myeloid leukemia (AML) patients. Based on our hypothesis that this clinical resistance to ondansetron is associated with ABCB1 genetic polymorphisms, we investigated whether ABCB1 gene variations affect the efficacy of ondansetron in chemotherapy-induced nausea and vomiting.
Related JoVE Video
Huperzine A ameliorates cognitive deficits in streptozotocin-induced diabetic rats.
Int J Mol Sci
PUBLISHED: 02-24-2014
Show Abstract
Hide Abstract
The present study was designed to probe the effects of Huperzine A (HupA) on diabetes-associated cognitive decline (DACD) using a streptozotocin (STZ)-injected rat model. Diabetic rats were treated with HupA (0.05 and 0.1 mg/kg) for seven weeks. Memory functions were evaluated by the water maze test. Nissl staining was selected for detecting neuronal loss. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) were analyzed by ELISA and real-time PCR, respectively. The activities of choline acetylase (ChAT), Acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), NF-?B p65 unit, TNF-?, IL-1?, IL-6 and caspase-3 were measured using corresponding kits. After seven weeks, diabetic rats exhibited remarkable reductions in: body weight, percentage of time spent in target quadrant, number of times crossing the platform, ChAT and BDNF levels, SOD, GSH-Px and CAT accompanied with increases in neuronal damage, plasma glucose levels, escape latency, mean path length, AChE, MDA level as well as CAT, NF-?B p65 unit, TNF-?, IL-1?, IL-6 and caspase-3 in cerebral cortex and hippocampus. Supplementation with HupA significantly and dose-dependently reversed the corresponding values in diabetes. It is concluded that HupA ameliorates DACD via modulating BDNF, oxidative stress, inflammation and apoptosis.
Related JoVE Video
JAZF1 can regulate the expression of lipid metabolic genes and inhibit lipid accumulation in adipocytes.
Biochem. Biophys. Res. Commun.
PUBLISHED: 02-19-2014
Show Abstract
Hide Abstract
JAZF1 is a newly identified gene with unknown functions. A recent genome-wide association study showed that JAZF1 is associated with type 2 diabetes and is highly expressed in liver and adipose tissue. Studies have demonstrated that JAZF1 is the co-repressor for nuclear orphan receptor TAK1, whereas most nuclear orphan receptor family members are involved in the regulation of lipid metabolism. Therefore, JAZF1 could be closely related to glycolipid metabolism. In this study, JAZF1 was significantly upregulated during the induced differentiation process of 3T3-L1 preadipocytes. The overexpression of JAZF1 inhibited lipid accumulation in differentiated mature 3T3-L1 adipocytes and significantly inhibited the expression of SREBPl, ACC, and FAS, which were important in lipid synthesis, while upregulating the expression of key enzyme hormone-sensitive lipase in lipoclasis. Moreover, SREBPl exhibited an inhibitory function on the expression of JAZF1. SREBP1 reversed the inhibitory action on lipid accumulation of JAZF1. SREBP1 and JAZF1 were observed to regulate each other in adipocytes. Therefore, JAZF1 could regulate the expression of particular genes related to lipid metabolism and inhibit lipid accumulation in adipocytes. This result suggests that JAZF1 may be a potential target for the treatment of diseases, such as obesity and lipid metabolism disorders.
Related JoVE Video
Preferential induction of CYP1A1 over CYP1B1 in human breast cancer MCF-7 cells after exposure to berberine.
Asian Pac. J. Cancer Prev.
PUBLISHED: 02-18-2014
Show Abstract
Hide Abstract
Estrogens are considered the major breast cancer risk factor, and the carcinogenic potential of estrogens might be attributed to the DNA modification caused by derivatives formed during metabolism. 17?-estradiol (E2), the main steroidal estrogen present in women, is metabolized via two major pathways: formation of the 2-hydroxyestradiol (2-OH E2) and 4-hydroxyestradiol (4-OH E2) through the action of Cytochrome P450 (CYP) 1A1 and 1B1, respectively. Previous reports suggested that 2-OH E2 have putative protective effects, while 4-OH E2 is genotoxic and has potent carcinogenic activity. Thus, the ratio of 2-OH E2/4-OH E2 is a critical determinant of the toxicity of E2 in mammary cells. In the present study, we investigated the effects of the berberine on the expression profile of the estrogen metabolizing enzymes CYP1A1 and CYP1B1 in breast cancer MCF-7 cells. Berberine treatment produced significant induction of both forms at the level of mRNA expression, but with increased doses produced 16~ to 52~fold greater inductions of CYP1A1 mRNA over CYP1B1 mRNA. Furthermore, berberine dramatically increased CYP1A1 protein levels but did not influence CYP1B1 protein levels in MCF-7 cells. In conclusion, we present the first report to show that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1, could redirect E2 metabolism in a more protective pathway in the breast cancer MCF-7 cells.
Related JoVE Video
The ATP7B genetic polymorphisms predict clinical outcome to platinum-based chemotherapy in lung cancer patients.
Tumour Biol.
PUBLISHED: 02-17-2014
Show Abstract
Hide Abstract
This study aims to investigate the influence of ATP7B genetic polymorphism to platinum-based chemotherapy in Chinese Han lung cancer patients. A total of 338 Chinese Han lung cancer patients were enrolled in this study. All patients underwent at least two cycles of platinum-based chemotherapy. Four tag SNPs of ATP7B (rs1061472, rs9535826, rs7999812, and rs9535828) were selected to evaluate their impacts to platinum-based chemotherapy in these patients. ATP7B rs9535828 and rs9535826 were found to be associated with platinum resistance in Chinese Han lung cancer patients. Patients with A allele in ATP7B rs9535828 presented an increased susceptibility to platinum drugs (OR 1.96, 95 % CI 1.17-3.30, p?
Related JoVE Video
Lignans from the bark of Eucommia ulmoides inhibited Ang II-stimulated extracellular matrix biosynthesis in mesangial cells.
Chin Med
PUBLISHED: 02-11-2014
Show Abstract
Hide Abstract
Tree bark of Eucommia ulmoides Oliv., (commonly well-known as "Du-zhong" in China), has been used to treat hypertension, hypercholesterolemia, hyperglycemia, hepatic fibrosis and renal injury. This study aims to investigate the effects of lignans extracted from the bark of Eucommia ulmoides Oliv. on Ang II-induced proliferation and extracellular matrix biosynthesis in rat mesangial cells.
Related JoVE Video
ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis.
Drug Metab. Pharmacokinet.
PUBLISHED: 02-11-2014
Show Abstract
Hide Abstract
The effects of genetic polymorphisms of ABCB1 C3435T, POR*28, CYP3A4*1G and CYP3A5*3 variants and gender relating to metabolism on the exposure and response of amlodipine in Chinese hypertensive patients were determined. Population pharmacokinetic analyses were performed on data which were collected prospectively from 60 Chinese patients with mild to moderate essential hypertension [age range 40-74 years, males (n = 31), females (n = 29)] receiving oral racemic amlodipine for 4 weeks. Blood pressure was evaluated at the end of weeks 0 and 4. Blood samples were collected in heparinized tubes at the following times: 0, 2, 6, and 24 h on about day 28 after administration of amlodipine. A one-compartment model with first-order elimination and absorption best described the amlodipine pharmacokinetic data. ABCB1 3435 genetic polymorphism and gender affect the amlodipine oral clearance (CL/F). CL/F (L/h) = 28.8 × (1 + GNDR)(-0.531) × (ABCB1 C3435T) where GNDR = 0 and 1 are for male and female, respectively. The CL/F value in a male patient with the ABCB1 3435CC or CT genotype is 28.8 L/h. Lower CL/F and higher exposure occurs in female subjects with the ABCB1 3435CC or CT genotype who have greater decreases in blood pressure after treatment with amlodipine. The results may help to improve the efficacy and tolerability of amlodipine in essential hypertensive patients.
Related JoVE Video
Diverse solid tumors expressing a restricted epitope of L1-CAM can be targeted by chimeric antigen receptor redirected T lymphocytes.
J. Immunother.
PUBLISHED: 02-11-2014
Show Abstract
Hide Abstract
Adhesion molecule L1-CAM (CD171) was originally reported to be overexpressed on neuroblastoma and to play an important role during tumor progression. More recently, it has been shown to be overexpressed on many other solid tumors such as melanoma and carcinomas of the cervix, ovary, bladder, and others. Thus, there has been a growing interest in using this cell-surface molecule as a target for both antibody-based and cellular-based therapy-our group has previously examined the clinical utility of chimeric antigen receptor (CAR)-redirected cytolytic T cells that specifically target the CE7 epitope of L1-CAM on neuroblastoma patients. Here, we sought to determine whether this CE7 epitope is present on other recently identified L1-CAM tumors and whether it too can be targeted by CAR T cells. Our studies demonstrate that a diverse array of human tumor cell lines and primary solid tumors (ovarian, lung, and renal carcinoma, glioblastoma and neuroblastoma) do express the CE7 epitope and can efficiently stimulate CE7-specific CAR-redirected (CE7R) T-cell lytic activity and secretion of proinflamatory cytokines. L1-CAM was also detected on a limited number of normal tissues; however, L1-CAM expressed on normal human monocytes was not bound by the CE7 mAb nor was it targeted by CE7R T cells, suggesting that the CE7 epitope is more tumor restricted and not expressed on all L1-CAM tissues. Overall, the CE7 epitope of L1-CAM on a variety of tumors may be amenable to targeting by CE7R T cells, making it a promising target for adoptive immunotherapy.
Related JoVE Video
Pretreatment with antiasthmatic drug ibudilast ameliorates A? 1-42-induced memory impairment and neurotoxicity in mice.
Pharmacol. Biochem. Behav.
PUBLISHED: 01-18-2014
Show Abstract
Hide Abstract
Amyloid-? peptide (A?) is thought to be associated with the progressive neuronal death observed in Alzheimer's disease (AD). However, effective neuroprotective approaches against A? neurotoxicity are unavailable. Here, we investigated possible preventive effects of ibudilast, as a pharmacologic phosphodiesterase inhibitor, currently used for treatment of inflammatory diseases such as asthma, on A? 1-42-induced neuroinflammatory, apoptotic responses and memory impairment. We found that pretreatment with ibudilast (4 or 12 mg/kg, i.p.) significantly ameliorated impaired spatial learning and memory in intracerebroventricularly (ICV) A? 1-42-injected mice, as evidenced by decrease in escape latency during acquisition trials and increase in exploratory activities in the probe trial in Morris water maze (MWM) task, and by increase in the number of correct choices and decrease in latency to enter the shock-free compartment in Y-maze test. Further study showed that ibudilast prevented generation of pro-inflammatory cytokines such as NF-?B p65 and TNF-? as well as pro-apoptotic molecule caspase-3 activation and anti-apoptotic protein Bcl-2 downregulation in both hippocampus and cortex of ICV A? 1-42-injected mice. Taken together, our findings suggest that ibudilast has preventive effects on A?-induced cognitive impairment via inhibiting neuroinflammatory and apoptotic responses.
Related JoVE Video
Nrf2 protects against furosemide-induced hepatotoxicity.
Toxicology
PUBLISHED: 01-17-2014
Show Abstract
Hide Abstract
Furosemide is a diuretic drug, but its reactive intermediates lead to acute liver injury in mice. Given the essential role of Nrf2 as a cellular defense regulator, we investigated whether Nrf2 would protect against furosemide-induced liver injury using the Nrf2 "gene-dose response" mouse model (Nrf2-null with Nrf2 knock-out, wild-type with normal expression of Nrf2, Keap1-KD with enhanced Nrf2 activation and Keap1-HKO mice with maximum Nrf2 activation). Twenty-four hours after furosemide administration (250mg/kg, i.p.), serum ALT activities and histopathological analysis indicated severe hepatotoxicity in Nrf2-null and WT mice, but significantly less in the Nrf2-overexpressing Keap1-KD and Keap1-HKO mice. Furosemide increased the mRNA of genes involved in the acute phase response (hemeoxygenase-1 and metallothionein-1), ER stress (C/Ebp-homologous protein and Growth arrest and DNA-damage-inducible protein), inflammatory cytokine (interleukin 1 beta), chemokines (macrophage inflammatory protein 2 and mouse keratinocyte-derived chemokine), as well as apoptosis (early growth response factor and BCL2-associated X protein) in livers of Nrf2-null and wild-type mice, but these genes increased less in mice with more Nrf2. The two genotypes of over-expressed Nrf2 mice had increased expression of the Nrf2 target genes Gclm, Gclc and Nqo1 prior to furosemide administration, and the expressions of these genes were increased further after furosemide administration. Thus, our findings provide strong evidence that over-expression of Nrf2 in Keap1-KD and Keap1-HKO mice and the increases in mRNA of a number of genes involved in anti-oxidative stress, anti-inflammation, anti-ER stress and anti-apoptosis protect against furosemide-induced hepatotoxicity.
Related JoVE Video
Association of platelet ITGA2B and ITGB3 polymorphisms with ex vivo antiplatelet effect of ticagrelor in healthy Chinese male subjects.
Int. J. Hematol.
PUBLISHED: 01-14-2014
Show Abstract
Hide Abstract
Ticagrelor (TIC) is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect by indirect inhibition of the GPIIb/IIIa complex. Polymorphisms in genes coding GPIIb/IIIa, namely ITGA2B and ITGB3, are associated with aspirin resistance and risk for thrombotic diseases. We assessed whether ITGA2B and ITGB3 polymorphisms can influence the ex vivo antiplatelet activity of ticagrelor in Chinese population. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined using optical aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 ?M ticagrelor, respectively. Single nucleotide polymorphisms in ITGA2B (rs5911 G>T) and ITGB3 (rs4642 A>G and rs4634 G>A) were genotyped by sequencing. TIC at both concentrations of 15 and 50 ?M decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). As compared to ITGA2B rs5911 GG homozygotes, individuals with the rs5911 TG genotype showed significantly increased inhibition of platelet aggregation (IPA) by both 15 and 50 ?M ticagrelor incubation (P < 0.05, respectively). Neither rs4642 nor rs4634 polymorphism affected ticagrelor-induced IPA. We suggest that the ITGA2B rs5911 GG genotype is associated with decreased ex vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects.
Related JoVE Video
Puerarin protects endothelial cells from oxidized low density lipoprotein induced injuries via the suppression of LOX-1 and induction of eNOS.
Can. J. Physiol. Pharmacol.
PUBLISHED: 01-10-2014
Show Abstract
Hide Abstract
Oxidized low density lipoprotein (oxLDL) induced injury of endothelial cells is considered to be the first step in the pathogenesis of atherosclerosis. This study aimed to investigate some of the effects and mechanisms of puerarin on oxLDL-induced endothelial injuries. We measured cell viability, and the release of lactate dehydrogenase (LDH), nitric oxide (NO), and interleukin-8 (IL-8) to evaluate the protective effects of puerarin. Intracellular reactive oxygen species (ROS) were detected using 2',7'-dichlorofluorescein diacetate (DCFH-DA). The expression of lectin-like low-density lipoprotein receptor-1 (LOX-1), endothelial nitric oxide synthase (eNOS), cyclooxygenase 2 (COX-2), p38MAPK, and protein kinase B (PKB) phosphorylation, nuclear factor-?B (NF-?B) nuclear translocation, and inhibitor of ?B (I?B) degradation were detected using quantitative real-time PCR or Western blot. The results showed that oxLDL significantly decreased cell viability, increased LDH and IL-8 release, inhibited NO production, and induced COX-2 expression. Pretreatment with puerarin led to a strong inhibition of these effects. OxLDL stimulated the expression of LOX-1, the overproduction of ROS, the phosphorylation of p38MAPK, the dephosphorylation of PKB, activation of NF-?B, and the degradation of I?B. These oxLDL-induced effects were suppressed after puerarin pretreatment. These results suggest that puerarin inhibits oxLDL-induced endothelial cell injuries, at least in part, via inhibition of the LOX-1-mediated p38MAPK-NF-?B inflammatory and the PKB-eNOS signaling pathways.
Related JoVE Video
Validation of a liquid chromatography-electrospray ionization-tandem mass spectrometry method for determination of all-trans retinoic acid in human plasma and its application to a bioequivalence study.
Molecules
PUBLISHED: 01-07-2014
Show Abstract
Hide Abstract
A sensitive, reliable and specific LC-MS-MS method was developed and validated for the identification and quantitation of all-trans retinoic acid (ATRA) in human plasma. Acitretin was used as the internal standard (IS). After liquid-liquid extraction of 500 ?L plasma with methyl tert-butyl ether (MTBE), ATRA and the IS were chromatographed on a HyPURITY C18 column (150 mm×2.1 mm, 5 ?m) with the column temperature set at 40 °C. The mobile phase was consisted of 40% phase A (MTBE-methanol-acetic acid, 50:50:0.5, v/v) and 60% phase B (water-methanol-acetic acid, 50:50:0.5, v/v) with a flow rate of 0.3 mL/min. The API 4000 triple quadrupole mass spectrometer was operated in multiple reaction monitoring (MRM) mode via the positive electrospray ionization interface using the transition m/z 301.4?123.1 for ATRA and m/z 326.9?177.1 for IS, respectively. The calibration curve was linear over the range of 0.45-217.00 ng/mL (r?0.999) with a lower limit of quantitation (LLOQ) of 0.45 ng/mL. The intra- and inter-day precisions values were below 8% relative standard deviation and the accuracy was from 98.98% to 106.19% in terms of relative error. The validated method was successfully applied in a bioequivalence study of ATRA in Chinese healthy volunteers.
Related JoVE Video
Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates A?1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice.
Neuropharmacology
PUBLISHED: 01-06-2014
Show Abstract
Hide Abstract
Montelukast, known as a cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is currently used for treatment of inflammatory diseases such as asthma. Here, we investigated effects of montelukast on neuroinflammatory, apoptotic responses, and memory performance following intracerebral infusions of amyloid-? (A?). The data demonstrated that intracerebroventrical infusions of aggregated A?1-42 (410 pmol/mouse) produced deficits in learning ability and memory, as evidenced by increase in escape latency during acquisition trials and decreases in exploratory activities in the probe trial in Morris water maze (MWM) task, and by decrease in the number of correct choices and increase in latency to enter the shock-free compartment in Y-maze test, and caused significant increases in pro-inflammatory cytokines such as NF-?B p65, TNF-? and IL-1? as well as pro-apoptotic molecule caspase-3 activation and anti-apoptotic protein Bcl-2 downregulation in hippocampus and cortex. Interestingly, this treatment resulted in upregulation of protein or mRNA of CysLT1R in both hippocampus and cortex. Blockade of CysLT1R by repeated treatment with montelukast (1 or 2 mg/kg, ig, 4 weeks) reduced A?1-42-induced CysLT1R expression and also suppressed A?1-42-induced increments of NF-?B p65, TNF-?, IL-1? and caspase-3 activation, and Bcl-2 downregulation in the hippocampus and cortex. Correspondingly, montelukast treatment significantly improved A?1-42-induced memory impairment in mice, but had little effect on normal mice. Our results show that montelukast may ameliorate A?1-42-induced memory impairment via inhibiting neuroinflammation and apoptosis mediated by CysLT1R signaling, suggesting that CysLT1R antagonism represents a novel treatment strategy for Alzheimer's disease.
Related JoVE Video
Protective effects of let-7a and let-7b on oxidized low-density lipoprotein induced endothelial cell injuries.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Lectin-like low-density lipoprotein receptor 1 (LOX-1) is a receptor for oxidized low density lipoprotein (oxLDL) in endothelial cells. The activation of LOX-1 by oxLDL stimulates the apoptosis and dysfunction of endothelial cells, and contributes to atherogenesis. However, the regulatory factors for LOX-1 are still unclear. MicroRNAs are small, endogenous, non-coding RNAs that regulate gene expressions at a post-transcriptional level. The let-7 family is the second microRNA been discovered, which plays important roles in cardiovascular diseases. Let-7a and let-7b were predicted to target LOX-1 3'-UTR and be highly expressed in endothelial cells. The present study demonstrated that LOX-1 was a target of let-7a and let-7b. They inhibited the expression of LOX-1 by targeting the positions of 310-316 in LOX-1 3'-UTR. Over-expression of let-7a and let-7b inhibited the oxLDL-induced endothelial cell apoptosis, NO deficiency, ROS over-production, LOX-1 upregulation and endothelial nitric oxide synthase (eNOS) downregulation. Moreover, we found that oxLDL treatment induced p38MAPK phosphorylation, NF-?B nuclear translocation, I?B degradation and PKB dephosphorylation. Let-7a or let-7b over-expression attenuated these alterations significantly. The present study may provide a new insight into the protective properties of let-7a and let-7b in preventing the endothelial dysfunction associated with cardiovascular disease, such as atherosclerosis.
Related JoVE Video
The prognostic value of altered eIF3a and its association with p27 in non-small cell lung cancers.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Over-expressed eukaryotic initiation factor 3a (eIF3a) in non-small cell lung cancer (NSCLC) contributed to cisplatin sensitivity. However, the role of eIF3a in oncogenesis was still controversial. This study was designed to investigate the prognostic impact of eIF3a and p27 in radically resected NSCLC patients.
Related JoVE Video
Acupuncture promotes angiogenesis after myocardial ischemia through H3K9 acetylation regulation at VEGF gene.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Acupuncture exerts cardioprotective effects on several types of cardiac injuries, especially myocardial ischemia (MI), but the mechanisms have not yet been well elucidated. Angiogenesis mediated by VEGF gene expression and its modification through histone acetylation has been considered a target in treating myocardial ischemia. This study aims to exam whether modulation of angiogenesis through H3K9 acetylation regulation at VEGF gene is one possible cardioprotective mechanism of acupuncture.
Related JoVE Video
The association of transporter genes polymorphisms and lung cancer chemotherapy response.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Lung cancer is one of the most common cancers and is the leading cause of death worldwide. Platinum-based chemotherapy is the main treatment method in lung cancer patients. Our previous studies indicated that single nucleotide polymorphisms (SNPs) in some transporter genes played important role in platinum-based chemotherapy efficacy. The aim of this study was to investigate the association of SNPs in transporter genes and platinum-based chemotherapy efficacy. The main polymorphisms on transporters OCT2, LRP, AQP2, AQP9 and TMEM205 genes were genotyped in 338 lung cancer patients. The rs195854 in genotypic model, rs896412 in genotypic and recessive models for all subjects showed significant association with chemotherapy response. In stratification analysis, TMEM205 rs896412, OCT2 rs1869641 and rs195854, AQP9 rs1516400 and AQP2 rs7314734 showed significant relation to chemotherapy response. In conclusion, the genetic polymorphisms in OCT2, AQP2, AQP9 and TMEM205 may contribute to chemotherapy response in lung cancer patients.
Related JoVE Video
Endothelial nitric oxide synthase gene G894T polymorphism and myocardial infarction: a meta-analysis of 34 studies involving 21,068 subjects.
PLoS ONE
PUBLISHED: 01-01-2014
Show Abstract
Hide Abstract
Researches have revealed that the endothelial nitric oxide synthase (eNOS) gene G894T polymorphism is associated with the risk of Myocardial infarction (MI), but the results remain conflicting.
Related JoVE Video
Genomic screening for targets regulated by berberine in breast cancer cells.
Asian Pac. J. Cancer Prev.
PUBLISHED: 12-03-2013
Show Abstract
Hide Abstract
Berberine, a common isoquinoline alkaloid, has been shown to possess anti-cancer activities. However, the underlying molecular mechanisms are still not completely understood. In the current study, we investigated the effects of berberine on cell growth, colony formation, cell cycle distribution, and whether it improved the anticancer efficiency of cisplatin and doxorubicin in human breast cancer estrogen receptor positive (ER+) MCF-7 cells and estrogen receptor negative (ER-) MDA-MB-231 cells. Notably, berberine treatment significantly inhibited cell growth and colony formation in the two cell lines, berberine in combination with cisplatin exerting synergistic growth inhibitory effects. Accompanied by decreased growth, berberine induced G1 phase arrest in MCF-7 but not MDA-MB-231 cells. To provide a more detailed understanding of the mechanisms of action of berberine, we performed genome-wide expression profiling of berberine-treated cells using cDNA microarrays. This revealed that there were 3,397 and 2,706 genes regulated by berberine in MCF-7 and MDA-MB-231 cells, respectively. Fene oncology (GO) analysis identified that many of the target genes were involved in regulation of the cell cycle, cell migration, apoptosis, and drug responses. To confirm the microarray data, qPCR analysis was conducted for 10 selected genes based on previously reported associations with breast cancer and GO analysis. In conclusion, berberine exhibits inhibitory effects on breast cancer cells proliferation, which is likely mediated by alteration of gene expression profiles.
Related JoVE Video
Protective effect of pranlukast on A? 1-42-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1.
Int. J. Neuropsychopharmacol.
PUBLISHED: 11-11-2013
Show Abstract
Hide Abstract
Deposition of extracellular amyloid-? (A?) peptide is one of the pathological hallmarks of Alzheimers disease (AD). Accumulation of A? is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against A? neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, on the impairment of learning and memory formation induced by A? and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of A? 1-42 resulted in a significant decline of spatial learning and memory of mice in the Morris water maze (MWM) and Y-maze tests, together with a serious depression of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of the mice. Importantly, this treatment caused significant increases in CysLT1R expression and subsequent NF-?B signaling, caspase-3 activation and Bcl-2 downregulation in the hippocampus or prefrontal cortex. Oral administration of pranlukast at 0.4 or 0.8 mg/kg for 4 wk significantly reversed A? 1-42-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed A? 1-42-induced CysLT1R upregulation, and markedly suppressed the A? 1-42-triggered NF-?B pathway, caspase-3 activation and Bcl-2 downregulation in the hippocampus and prefrontal cortex in mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay confirmed its presence in the brain after oral administration of pranlukast in mice. These data disclose novel findings about the therapeutic potential of pranlukast, revealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.
Related JoVE Video
Preparation and functionalization of graphene nanocomposites for biomedical applications.
Nat Protoc
PUBLISHED: 11-07-2013
Show Abstract
Hide Abstract
Functionalized nano-graphene- and graphene-based nanocomposites have gained tremendous attention in the area of biomedicine in recent years owing to their biocompatibility, the ease with which they can be functionalized and their properties such as thermal and electrical conductivity. Potential applications for functionalized nanoparticles range from drug delivery and multimodal imaging to exploitation of the electrical properties of graphene toward the preparation of biosensing devices. This protocol covers the preparation, functionalization and bioconjugation of various graphene derivatives and nanocomposites. Starting from graphite, the preparations of graphene oxide (GO), reduced GO (RGO) and magnetic GO-based nanocomposite, as well as how to functionalize them with biocompatible polymers such as polyethylene glycol (PEG), are described in detail. We also provide procedures for (125)I radiolabeling of PEGylated GO and the preparation of GO-based gene carriers; other bioconjugation approaches including drug loading, antibody conjugation and fluorescent labeling are similar to those described previously and used for bioconjugation of PEGylated carbon nanotubes. We hope this article will help researchers in this field to fabricate graphene-based bioconjugates with high reproducibility for various applications in biomedicine. The sample preparation procedures take various times ranging from 1 to 2 d.
Related JoVE Video
In vivo tumor targeting and image-guided drug delivery with antibody-conjugated, radiolabeled mesoporous silica nanoparticles.
ACS Nano
PUBLISHED: 10-01-2013
Show Abstract
Hide Abstract
Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anticancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and (64)Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that (64)Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy.
Related JoVE Video
Let-7 in cardiovascular diseases, heart development and cardiovascular differentiation from stem cells.
Int J Mol Sci
PUBLISHED: 09-24-2013
Show Abstract
Hide Abstract
The let-7 family is the second microRNA found in C. elegans. Recent researches have found it is highly expressed in the cardiovascular system. Studies have revealed the aberrant expression of let-7 members in cardiovascular diseases, such as heart hypertrophy, cardiac fibrosis, dilated cardiomyopathy (DCM), myocardial infarction (MI), arrhythmia, angiogenesis, atherosclerosis, and hypertension. Let-7 also participates in cardiovascular differentiation of embryonic stem cells. TLR4, LOX-1, Bcl-xl and AGO1 are by now the identified target genes of let-7. The circulating let-7b is suspected to be the biomarker of acute MI and let-7i, the biomarker of DCM. Further studies are necessary for identifying the gene targets and signaling pathways of let-7 in cardiovascular diseases. Let-7 might be a potential therapeutic target for cardiovascular diseases. This review focuses on the research progresses regarding the roles of let-7 in cardiovascular development and diseases.
Related JoVE Video
Effect of NR3C2 genetic polymorphisms on the blood pressure response to enalapril treatment.
Pharmacogenomics
PUBLISHED: 09-23-2013
Show Abstract
Hide Abstract
Aim: The mineralocorticoid receptor (MR; also known as NR3C2) plays important roles in the modulation of blood pressure. The effect of NR3C2 polymorphisms on antihypertensive response to enalapril was investigated. Patients & methods: Two hundred and seventy nine essential hypertension patients treated with enalapril were genotyped for two NR3C2 tagSNPs, rs5522 and rs2070950, by Sequenom MassArray™ technology. Results: The reductions in diastolic blood pressure (DBP) were significantly greater in AA homozygotes compared with AG+GG genotype carriers for the rs5522 polymorphism (p = 0.009), and the reductions in DBP were greater in GG homozygotes compared with GC+CC genotype carriers for the rs2070950 polymorphism, with marginal significance (p = 0.065). Stepwise multiple regression analysis indicated that significant predictors of DBP reduction were baseline DBP (p < 0.001), waist:hip ratio (p = 0.001) and rs5522 genotype (p = 0.003). Conclusion:NR3C2 rs5522 affects blood pressure response to enalapril treatment and may serve as a useful pharmacogenomic marker of antihypertensive response to enalapril in essential hypertension patients. Original submitted 8 August 2013; Revision submitted 29 August 2013.
Related JoVE Video
Pravastatin stimulates angiogenesis in a murine hindlimb ischemia model: a positron emission tomography imaging study with (64)Cu-NOTA-TRC105.
Am J Transl Res
PUBLISHED: 09-10-2013
Show Abstract
Hide Abstract
In this study, (64)Cu-NOTA-TRC105 (TRC105 is an anti-CD105 monoclonal antibody that binds to both human and murine CD105) positron emission tomography (PET) was used to assess the response to pravastatin treatment in a murine model of peripheral artery disease (PAD). Hindlimb ischemia was induced by ligation of the right femoral arteries in BALB/c mice under anesthesia, and the left hindlimb served as an internal control. Mice in the treatment group were given intraperitoneal pravastatin daily until the end of the study, whereas the animals in the control group were injected with 0.9% sodium chloride solution. Laser Doppler imaging showed that blood flow in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 10 in the treatment group and on day 20 in the control group. Angiogenesis was non-invasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 3, 10, 17, and 24. Tracer uptake at 48 h post-injection in the ischemic hindlimb in the treatment group was significantly higher than that of the control group on day 10 (20.5 ± 1.9 %ID/g vs 11.4 ± 1.5 %ID/g), suggesting increased CD105 expression and higher level of angiogenesis upon pravastatin treatment, and gradually decreased to background levels in both groups (4.9 ± 0.8 %ID/g vs 3.4 ± 1.9 %ID/g on day 24). The in vivo PET data correlated well with ex vivo biodistribution studies performed on day 24. Increased CD105 expression on days 3 and 10 following ischemia was further confirmed by immunofluorescence staining. Taken together, our results indicated that (64)Cu-NOTA-TRC105 PET is a suitable and non-invasive method to monitor the angiogenesis and therapeutic response in PAD, which can also be utilized for non-invasive evaluation of other pro-angiogenic/anti-angiogenic drugs in other cardiovascular diseases and cancer.
Related JoVE Video
Hypertensive cardiac remodeling effects of lignan extracts from Eucommia ulmoides Oliv. bark--a famous traditional Chinese medicine.
Am. J. Chin. Med.
PUBLISHED: 07-31-2013
Show Abstract
Hide Abstract
The lignan extracts from the tree bark of Eucommia ulmoides Oliv., a famous traditional Chinese medicine, have been demonstrated to have inhibitory effects on aldose reductase activity in spontaneously hypertensive rat myocardium. This study was aimed to investigate the hypertensive cardiac remodeling effects of the lignan extracts together with epalrestat. Ten-week-old male spontaneously hypertensive rats were randomly divided into three groups (n = 12, each) and administered 100 mg/kg/d of captopril (angiotensin converting enzyme inhibitor), 100 mg/kg/d of epalrestat (aldose reductase inhibitor) or 300 mg/kg/d of lignan extracts by gavage for 16 weeks. Sex-, age-, and number-matched normotensive Wistar Kyoto rats with spontaneously hypertensive rats were treated with distilled water (vehicle) as controls. Systolic blood pressures were measured periodically. Echocardiography examination was taken when rats were 24 weeks old. We found that both captopril and lignan extracts lowered blood pressure, and inhibited aldose reductase activity similarly to epalrestat. Echocardiography examination and histomorphometry indices were improved in all treated groups (p < 0.05). Therefore, lignan extracts could prevent hypertensive cardiac remodeling, which is likely related to aldose reductase inhibition.
Related JoVE Video
Chelator-Free Synthesis of a Dual-Modality PET/MRI Agent.
Angew. Chem. Int. Ed. Engl.
PUBLISHED: 07-19-2013
Show Abstract
Hide Abstract
Old technique, new application: A simple and efficient chelator-free strategy for the synthesis of a novel dual-modality PET/MRI agent has been developed. Labeling of radioarsenic (*As(III) and *As(V) , *=71, 72, 74, 76) at the surface of superparamagnetic iron oxide nanoparticles (SPIONs) resulted in *As-SPIONs that can be used for simultaneous PET/MRI in cancer diagnosis, lymph-node mapping, and potentially for internal radiotherapy.
Related JoVE Video
Image-guided and tumor-targeted drug delivery with radiolabeled unimolecular micelles.
Biomaterials
PUBLISHED: 07-04-2013
Show Abstract
Hide Abstract
Unimolecular micelles formed by dendritic amphiphilic block copolymers poly(amidoamine)-poly(L-lactide)-b-poly(ethylene glycol) conjugated with anti-CD105 monoclonal antibody (TRC105) and 1,4,7-triazacyclononane-N, N, N-triacetic acid (NOTA, a macrocyclic chelator for (64)Cu) (abbreviated as PAMAM-PLA-b-PEG-TRC105) were synthesized and characterized. Doxorubicin (DOX), a model anti-cancer drug, was loaded into the hydrophobic core of the unimolecular micelles formed by PAMAM and PLA via physical encapsulation. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. TRC105-conjugated unimolecular micelles showed a CD105-associated cellular uptake in human umbilical vein endothelial cells (HUVEC) compared with non-targeted unimolecular micelles, which was further validated by cellular uptake in CD105-negative MCF-7 cells. In 4T1 murine breast tumor-bearing mice, (64)Cu-labeled targeted micelles exhibited a much higher level of tumor accumulation than (64)Cu-labeled non-targeted micelles, measured by serial non-invasive positron emission tomography (PET) imaging and confirmed by biodistribution studies. These unimolecular micelles formed by dendritic amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics.
Related JoVE Video
Involvement of cysteinyl leukotriene receptor 1 in A?1-42-induced neurotoxicity in vitro and in vivo.
Neurobiol. Aging
PUBLISHED: 06-27-2013
Show Abstract
Hide Abstract
Accumulation of amyloid-? (A?) is thought to be associated with the progressive neuronal death observed in Alzheimers disease, but the mechanisms underlying neurotoxicity triggered by A? remain elusive. In the current study, we investigated the roles of cysteinyl leukotriene receptor 1 (CysLT1R) in A?1-42-induced neurotoxicity in vitro or in vivo. In vitro exposure of mouse primary neurons to A?1-42 caused a gradual increases in CysLT1R expression. In vivo bilateral intrahippocampal injection of A?1-42 also elicited time-dependent increases of CysLT1R expression in the hippocampus and cortex of mice. The CysLT1R antagonist pranlukast not only reversed A?1-42-induced upregulation of CysLT1R, but also suppressed A?1-42-triggered neurotoxicity evidenced by enhanced nuclear factor-kappa B p65, activated caspase-3, decreased B-cell lymphoma-2 and cell viability and impaired memory. Furthermore, chronic treatment with pranlukast produced similar beneficial effects on memory behavior and hippocampal long-term potentiation to memantine or donepezil in intrahippocampal A?1-42-injected mice. Our data indicate that CysLT1R is involved in A?1-42-induced neurotoxicity, and that blockade of CysLT1R, such as application of CysLT1R antagonist, could be a novel and promising strategy for the treatment of Alzheimers disease.
Related JoVE Video
Gene-Wide Tagging Study of the Association Between KCNT1 Polymorphisms and the Susceptibility and Efficacy of Genetic Generalized Epilepsy in Chinese Population.
CNS Neurosci Ther
PUBLISHED: 06-25-2013
Show Abstract
Hide Abstract
The causes of genetic generalized epilepsies (GGEs) are still uncertain now. Some studies found that the human potassium channel, subfamily T, member 1 (KCNT1) is the candidate gene causing malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy which are all rare genetic generalized epilepsies. The aims of this study were going to evaluate the association between KCNT1 common variations and the susceptibility and drug resistance of genetic generalized epilepsies in Chinese population.
Related JoVE Video
Positron Emission Tomography Imaging of Angiogenesis in a Murine Hindlimb Ischemia Model with (64)Cu-Labeled TRC105.
Mol. Pharm.
PUBLISHED: 06-17-2013
Show Abstract
Hide Abstract
The goal of this study was to assess ischemia-induced angiogenesis with (64)Cu-NOTA-TRC105 positron emission tomography (PET) in a murine hindlimb ischemia model of peripheral artery disease (PAD). CD105 binding affinity/specificity of NOTA-conjugated TRC105 (an anti-CD105 antibody) was evaluated by flow cytometry, which exhibited no difference from unconjugated TRC105. BALB/c mice were anesthetized, and the right femoral artery was ligated to induce hindlimb ischemia, with the left hindlimb serving as an internal control. Laser Doppler imaging showed that perfusion in the ischemic hindlimb plummeted to ?20% of the normal level after surgery and gradually recovered to near normal level on day 24. Ischemia-induced angiogenesis was noninvasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 1, 3, 10, 17, and 24. (64)Cu-NOTA-TRC105 uptake in the ischemic hindlimb increased significantly from the control level of 1.6 ± 0.2 %ID/g to 14.1 ± 1.9 %ID/g at day 3 (n = 3) and gradually decreased with time (3.4 ± 1.9 %ID/g at day 24), which correlated well with biodistribution studies performed on days 3 and 24. Blocking studies confirmed the CD105 specificity of tracer uptake in the ischemic hindlimb. Increased CD105 expression on days 3 and 10 following ischemia was confirmed by histology and reverse transcription polymerase chain reaction (RT-PCR). This is the first report of PET imaging of CD105 expression during ischemia-induced angiogenesis. (64)Cu-NOTA-TRC105 PET may play multiple roles in future PAD-related research and improve PAD patient management by identifying the optimal timing of treatment and monitoring the efficacy of therapy.
Related JoVE Video
Pharmacokinetic issues of imaging with nanoparticles: focusing on carbon nanotubes and quantum dots.
Mol Imaging Biol
PUBLISHED: 05-30-2013
Show Abstract
Hide Abstract
With many desirable properties, nanoparticles hold tremendous potential for in vivo molecular imaging and improving the efficacy of small-molecule drugs. The pharmacokinetics (PK) and tissue distribution of nanoparticles largely define their in vivo performance and potential toxicity, which are fundamental issues that need to be elucidated. In this review article, we summarized how molecular imaging techniques (e.g., positron emission tomography, fluorescence imaging, etc.) can facilitate the investigation of PK profiles of nanoparticles using carbon nanotubes (CNTs) and quantum dots (QDs) as representative examples. Different imaging techniques can provide useful insights in monitoring the in vivo behavior and tissue distribution of these nanoparticles, and a number of strategies were utilized to optimize the PK profiles of CNTs and QDs. Based on the available literature reports, it can be concluded that chemical/physical properties of the nanoparticles (e.g., surface functionalization, hydrodynamic size, shape, surface charge, etc.), along with the administration routes/doses, can play critical roles in determining the PK and biodistribution pattern of nanoparticles. Robust chemistry for surface modification of nanoparticles is a prerequisite for successful future biomedical/clinical applications.
Related JoVE Video
Microscopic research on a multi-source traditional Chinese medicine, Astragali Radix.
J Nat Med
PUBLISHED: 05-27-2013
Show Abstract
Hide Abstract
Astragali Radix is a widely and commonly used Chinese herbal medicine, which is derived from roots of Astragalus membranaceus var. mongholicus and Astragalus membranaceus. To find a quick and reliable method of distinguishing these two species of Astragali Radix and of determining the age of a sample, microscopic characteristics of the two species were compared using light microscopy. The results showed that the microscopic characteristics, such as number of layers of phellem, continuing lignified xylem bundles within spring wood and lignified parenchyma cells in the central part of the xylem could be used for the differentiation of the root of A. membranaceus from the root of A. membranaceus var. mongholicus. Growth rings (annual rings) were found for the first time in the roots of both species, and could determine the age of a sample. For the first time, radial fibers in both species of Astragali Radix and pipette-shaped fibers in A. membranaceus var. mongholicus were found. The structure of "rotten heart" cork tissue (decayed central xylem) and tubular cork tissue was carefully studied, and the arranged order of tissues in both "rotten heart" and tubular cork tissues is phelloderm and phellem from outside to inside, which is contrary to that in the periderm.
Related JoVE Video
Cytochrome P450 oxidoreductase genetic polymorphisms A503V and rs2868177 do not significantly affect warfarin stable dosage in Han-Chinese patients with mechanical heart valve replacement.
Eur. J. Clin. Pharmacol.
PUBLISHED: 05-26-2013
Show Abstract
Hide Abstract
To investigate the influence of cytochrome P450 oxidoreductase (POR) polymorphisms (A503V and rs2868177) on warfarin stable dosage (WSD) in Han-Chinese patients with mechanical heart valve replacement (MHVR).
Related JoVE Video
Two novel functional single nucleotide polymorphisms of ADRB3 are associated with type 2 diabetes in the Chinese population.
J. Clin. Endocrinol. Metab.
PUBLISHED: 05-02-2013
Show Abstract
Hide Abstract
The purpose of this study was to investigate the association of two novel ?3-adrenergic receptor (ADRB3) gene polymorphisms (Ser165Pro and Ser257Pro) with type 2 diabetes (T2DM) in the Chinese population.
Related JoVE Video
Effect of a single-dose rifampin on the pharmacokinetics of pitavastatin in healthy volunteers.
Eur. J. Clin. Pharmacol.
PUBLISHED: 04-25-2013
Show Abstract
Hide Abstract
As an inhibitor of HMG-CoA reductase that catalyses the first step of cholesterol synthesis, pitavastatin undergoes little hepatic metabolism; however, it is a substrate of uptake and efflux transporters. Since pitavastatin is potentially co-administered with agents that affect transporter activities, the pharmacokinetics of pitavastatin was investigated on the effects of a single-dose rifampin in healthy volunteers.
Related JoVE Video
Pharmacokinetic comparison of the vasorelaxant compound ferulic acid following the administration of Guanxin II to healthy volunteers and patients with angina pectoris.
Exp Ther Med
PUBLISHED: 04-07-2013
Show Abstract
Hide Abstract
Coronary heart disease (CHD) is the leading cause of mortality worldwide. The Chinese medicinal formula Guanxin II has been shown to have a favorable effect in the attenuation of angina. The aim of this study was to compare the pharmacokinetics of ferulic acid (FA), which is a vasorelaxant compound present in Guanxin II, in healthy volunteers and patients with angina pectoris following the administration of Guanxin II. Ex vivo experiments were performed in order to investigate the vasorelaxant effect of FA on the human internal mammary artery (IMA) to provide evidence that it is a bioactive component of Guanxin II. Following the oral administration of Guanxin II, the FA levels in the serum were quantified by a simple and rapid high-performance liquid chromatography (HPLC) method. Treatment with FA (10(-8)-10(-3) M) caused a concentration-dependent relaxation of endothelial IMA rings following precontraction with KCl. Statistically significant differences were identified between the pharmaco-kinetic parameters Cmax, t1/2?, t1/2? and t1/2Ka of the healthy volunteers and the patients with angina pectoris following the oral administration of Guanxin II. FA is a bioactive compound absorbed from Guanxin II that attenuates angina pectoris, a condition that may modify the pharmacokinetics of FA. Not only do the pharmacokinetic parameters direct the clinical use of Guanxin II, but they may also be useful for exploring the pathology of angina pectoris.
Related JoVE Video
Let-7c inhibits NSCLC cell proliferation by targeting HOXA1.
Asian Pac. J. Cancer Prev.
PUBLISHED: 03-29-2013
Show Abstract
Hide Abstract
The aim of the present study was to explore mechanisms by which let-7c suppresses NSCLC cell proliferation.
Related JoVE Video
simple hit counter

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.